Comparing prostatic artery embolization to surgical and minimally invasive procedures for the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis

Background To summarize current evidence to report a comparative systematic review and meta-analysis of prostatic artery embolization (PAE) with transurethral resection of the prostate (TURP) and open simple prostatectomy (OSP) for the treatment of benign prostatic hyperplasia (BPH). Methods A systematic literature search was performed to identify studies published from inception until August 2021. The search terms used were (prostate embolization OR prostatic embolization) AND (prostatic hyperplasia OR prostatic obstruction) as well as the abbreviations of PAE and BPH. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool for observational studies. Random-effects meta-analysis was performed using Revman 5.4. Results Seven studies were included with 810 patients: five RCTs and one observational study compared PAE with TURP, and one observational study compared PAE with OSP. The included studies had considerable risk of bias concerns. TURP and OSP were associated with more statistically significant improvements in urodynamic measures and BPH symptoms compared to PAE. However, PAE seems to significantly improve erectile dysfunction compared to OSP and improve other outcome measures compared to TURP, although not significantly. PAE appeared to reduce adverse events and report more minor complications compared with TURP and OSP, but it is unclear whether PAE is more effective in the long-term. Conclusion PAE is an emerging treatment option for patients with symptomatic BPH who cannot undergo surgery or have undergone failed medical therapy. Overall, PAE groups reported fewer adverse events. Future ongoing and longer-term studies are needed to provide better insight into the benefit of PAE compared to other treatment options. Supplementary Information The online version contains supplementary material available at 10.1186/s12894-023-01397-1.


Background
Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate that often leads to lower urinary tract symptoms (LUTS) [1] BPH can put severe pressure on the urethra and bladder, which impairs bladder voiding [1].LUTS secondary to BPH can include a slow urinary stream, hesitancy, straining and can lead to serious complications including urinary retention, infection, and renal dysfunction [2].As males age, the prevalence of BPH increases, accounting for 60% of LUTS in males aged 50-60-years-old.Approximately 50% of men will develop BPH above 50 years of age, with an increase to 80% by age 80 [3,4].Although age is a main risk factor for BPH, other contributing factors might be metabolic syndrome, including hypertension and diabetes [3].Some males with BPH are asymptomatic and are not affected by this diagnosis; however, when symptomatic, this condition can critically impact an individuals' quality of life.Moderate to severe symptoms often require minimally invasive procedures to remove excess tissue or shrink the prostate gland [1,3].Medications such as alphablockers and 5-alpha-reductase inhibitors are common primary treatment options for BPH [5].Patients with symptoms refractory to these medical therapies may be subsequently treated with surgical procedures, such as transurethral resection of the prostate (TURP), which is recognized as the gold-standard [4].There are risks associated with the TURP procedure due to its surgical nature such as retrograde ejaculation, and patient outcomes are shown to be variable [1,4].In addition, open simple prostatectomy (OSP) is an alternative surgical technique to TURP used to treat LUTS secondary to BPH [6].OSP is thought to be more advantageous for men with moderate to severe LUTS and a prostate size that exceeds 80 mL [7,8].Notably, this technique may also be preferred when treating concomitant bladder stones as these can be extracted simultaneously [9].However, OSP has been associated with notable perioperative morbidity including bleeding complications, necessitating the introduction of newer and minimally invasive treatments [6].
Minimally invasive options for LUTS secondary to BPH have emerged, such as prostatic artery embolization (PAE) [3].PAE is an endovascular procedure where tiny particles are injected into the prostatic arteries to reduce blood flow to the prostate, causing it to shrink in size [10].A systematic review was performed to evaluate the available evidence on the clinical outcomes of PAE as it compares to other standard surgical interventions, namely TURP and OSP.

Search strategy and selection criteria
We performed a systematic literature search to identify relevant studies published from inception until August 2021.The search strategies were developed using controlled vocabulary and relevant keywords to prostatic artery embolization for BPH.The search terms used were (prostate embolization OR prostatic embolization) AND (prostatic hyperplasia OR prostatic obstruction) as well as the abbreviations of PAE and BPH.The primary search was conducted in PubMed, supplemented by searches in the Medline database and the Cochrane Central Register of Controlled Trials.
We included studies if they were (1) English-language full-text publications; (2) randomized controlled trials (RCTs) or prospective comparative non-randomized studies of participants with BPH; (3) included PAE interventions using any particle type, size, and embolization technique; (4) performed PAE through the femoral or radial artery.Acceptable comparators were surgical or minimally invasive procedures for BPH.We excluded (1) narrative reviews, retrospective studies, systematic reviews and meta-analyses, abstracts, editorials, case reports and commentaries; (2) non-comparative studies; (3) non-human studies.

Data abstraction and risk of bias assessment
Evidence included in this systematic review was acquired in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [11].Two independent reviewers extracted data from included studies, using a standardized form.Any discrepancies were resolved through discussion or, if necessary, adjudicated by a third reviewer (senior author).We evaluated the risk of bias using the Cochrane Collaboration [12] for randomized controlled trials and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) [13] tools for non-randomized studies for each individual study.

Outcome measures
The clinical outcomes of interest were prostate-specific antigen (PSA) levels, prostate volume (PV), post-void residual urine volume (PVR), and peak urinary flow rate (Qmax).Self-reported scores for international prostate symptom score (IPSS), health-related quality of life (QOL), and erectile function (IIEF) were included.A seven-question scale was used to rate international prostate symptom score (IPSS) urinary symptoms as mild, moderate, or severe [14].The IPSS health-related quality of life (IPSS-QOL) scale was used and ranges from 1 (delighted) to 6 (terrible), with a decrease in this score indicating improved QOL [14].Sexual outcomes were measured by International Index of Erectile Function (IIEF-5), a five-question scale to measure the degree of erectile dysfunction with a higher score indicating less erectile dysfunction [15].Secondary outcome measures included adverse events as reported by each study.

Synthesis
Studies were compared to evaluate for clinical and methodological heterogeneity and a meta-analysis was planned.Comparative analyses utilized the randomeffects model through RevMan 5.4 software.A metaanalysis was performed by grouping studies based on their study design.A two-tailed statistical test, with a 0.05 probability threshold for type 1 error, determined the statistical significance of the combined results.For continuous variables, the inverse variance method was applied, presenting treatment effects as mean differences (MD) alongside standard deviation (SD) of mean difference and 95% confidence intervals (CIs).To measure the extent of variance attributable to heterogeneity rather than chance, Higgins I 2 statistics were employed.
For outcomes with high clinical heterogeneity between study groups (different control treatments) or less than 2 studies per outcome, a meta-analysis was not performed.A summary of results were reported descriptively for these studies.

Assessing certainty of evidence
Based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology [16][17][18], the quality of evidence for each outcome was evaluated considering the five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.The body of evidence was categorized from high, moderate, low and very low certainty levels.
A detailed summary of functional outcome measures reported by each study is shown in the Additional file 1 (Supplementary Tables S1-S7).IIEF-5 [15] was used by all studies except for Insausti et al. [22] and Gao et al. [21] which did not assess erectile function in their studies.Three of the six included studies presented one year follow-up times.Abt et al. [19] and Gao et al. [21] had the longest follow-up of the included studies, with 24-month data comparing PAE with TURP.Baseline and 12-month follow-up outcomes are summarized for all studies except for Abt et al. [19] which did not report 12-month outcomes for the PV outcome measure only.

Risk of bias assessment of included studies
The assessment of bias varied across studies, despite studies addressing similar outcomes.Summaries of the risk of bias evaluations, conducted using the ROBINS-I and the Cochrane Collaboration's tool, are presented in (Fig. 2) and Table 2. Most randomized studies had a high overall risk of bias.

Critical appraisal of the evidence
The GRADE assessment of evidence provided by the included studies "very low to low" across all outcomes, indicating that "further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate" as well as "any estimate of the effect is very uncertain" [16][17][18].

Prostatic artery embolization (PAE) vs. open simple prostatectomy (OSP)
The study by Russo et al. [25] was the only eligible study offering a comparative analysis between PAE and OSP.Lastly, there was no information regarding pre-post procedural changes in PV between treatment arms.

Adverse events
Table 9 displays the adverse events categorized by Clavien-Dindo Grade in the included studies comparing PAE and TURP.The most common adverse event reported by all included studies comparing PAE and TURP was hematuria followed by urinary infection which was reported by all included studies except for Carnevale et al. [20] (Additional file 1: Table S8).Overall, 260 adverse events were reported in the PAE groups compared to 310 in the TURP groups (Additional file 1: Table S8).In all of the studies that reported it, urinary incontinence and ejaculatory disorders were higher in the TURP group compared to PAE except for one study by Ray et al. [24] Among the included studies comparing PAE with TURP, mainly minor (Clavien Grade I and II) adverse events were reported in the PAE group, compared to some major (Clavien Grade III and IV) events reported in the TURP group.In all of the included studies except for Gao et al. [21], TURP patients experienced more major complications than PAE patients, with PAE patients reporting none in two studies [20,22].When comparing PAE with OSP, PAE groups reported fewer adverse events overall [25].The most common adverse events for both PAE and OSP were Clavien grade I with the PAE treatment group reporting less events than OSP.One case of urinary infection (Clavien II) was reported on the PAE group compared to 3 cases post OSP.No Clavien grade IIIa complications (complications that require an intervention performed under local anesthesia) [22] were found in the PAE group, but 3.8% were reported for the OSP group.Namely, 2 cases of urethral stricture and 1 case of urgency and incontinence were reported as major complications in the OSP group.This study by Russo et al. [25] reported 7 overall adverse events for the PAE group compared to 24 events in the OSP group (Table 10).

Reintervention rate
The reintervention rates following PAE and TURP exhibit significant variability.PAE was associated with higher surgical reintervention rates.Notably, in the study by Abt et al. 2021 [19], 21% of patients undergoing initial PAE required subsequent TURP within two years for unsatisfactory outcomes, compared to a 7.8% surgical retreatment rate in the TURP cohort.Carnevale et al. [20] found that 13.3% of patients in the PAE group needed TURP reintervention post-PAE due to LUTS, whereas none in the TURP group required further intervention.Ray et al. [24] reported a total 20% reintervention for PAE (5% pre-12 months, 15% post-12 months), contrasting with 5.6% in TURP.Data on reintervention rates were not provided by Gao et al., Insausti et al.,, and Russo et al. [25] did not address this aspect when comparing PAE versus OSP.

Embolization particle size and radiation dose
From the embolization technique point of view, all PAEs were performed in a similar fashion.Most used embolic agents with particle size between 300 and 500 microns and similar embolic agent volume was administered.Abt et al. [19] used slightly smaller (250-400 microns), calibrated Embozene particles, but no significant differences in outcomes were reported.Two studies did not describe the amount of embolic used [22,24] and one study did not record the size of the particles used [24].Four out of the seven included studies reported radiation dose used during PAE, with two reporting the dose cumulatively (cGy/cm 2 ) [21,24] and two as mean dose (Gy/cm 2 ) [19,22].Table 11 presents the embolization particle sizes and PVs before and after intervention as well as the radiation dose administered during PAE.

Discussion
PAE is regarded as an effective, emerging treatment option for symptomatic BPH; however, its long-term clinical results are not as well established compared to other surgical procedures.This present meta-analysis highlights a comprehensive comparison of PAE and TURP across several clinical outcomes over a 12-month period.We found no significant difference in IPSS and QoL between PAE and TURP, indicating that both procedures are similarly effective in improving urinary symptoms and overall patient well-being.However, TURP was associated with a significantly better Qmax at 12 months compared to PAE.This was supported by a notable mean difference, despite high heterogeneity among the studies.Additionally, TURP led to a significant reduction in prostate volume, with moderate heterogeneity observed.These findings collectively suggest that while PAE and TURP offer comparable outcomes for symptom relief and quality of life, TURP might be more efficacious in improving certain functional parameters such as Qmax and prostate volume reduction at the 12-month follow-up.While significant improvements were reported for both PAE and TURP treatment groups, at short-term followup they are more notable in the TURP groups.This could be indicative of the procedural differences.The rapid symptomatic relief observed at 3-month follow-up in TURP patients is due to the procedure's immediate resection and ablation of prostatic tissue, contrasting with the delayed onset of benefits from PAE, which relies on ischemic reduction of the prostate and may take up to 6 months to manifest [26,27].This difference underscores the distinct mechanisms of action between TURP's direct tissue removal, yielding prompt improvement in LUTS, and PAE's gradual prostate volume reduction, leading to a slower but progressive alleviation of symptoms [28].
Two studies reported significant improvements to IPSS and IPSS-QoL in the TURP group when compared with PAE at 3 months [21] and 24 months [19].In addition, significant improvements to PV, PVR and Qmax were also reported at 3 months [19,21] and at 24 months [19] in the TURP group.While PAE did appear to improve some outcome measures, most were not significant.When comparing PAE with OSP, Russo et al. [25] reported significant improvements in IPSS, IPSS-QoL, Qmax, PVR and PSA levels at 12 months in the OSP group.In the same study, PAE seemed to significantly improve erectile dysfunction at 6 and 12 months [25] although more studies are needed to confirm the true benefit of PAE compared to OSP.
Overall, fewer adverse events were noted for PAE, and some were reported in the TURP group but absent from the PAE group.These differences might be explained by the minimally invasive nature of PAE compared to TURP and provides promising insight into the safety of this procedure for BPH.Furthermore, more minor (Clavien Grade I and II) events were reported for PAE compared to some major events (Clavien Grade III and IV) for TURP.Similarly, when comparing PAE with OSP, Russo et al. reported a greater incidence of major adverse events in the OSP group [25].These results corroborate those found in the literature which commonly report minor events after PAE such as hematospermia, urinary tract infections and dysuria [29].This finding can likely be explained in part by the reduced risk of more major events such as bleeding complications due to the lack of direct tissue resection in PAE.A previous meta-analysis investigating PAE further reported that 99% of complications were reported as minor out of a 33% overall complication rate [30].In addition, postoperative sexual dysfunction is more commonly reported in TURP patients, which has been associated with erectile nerve damage and heating from the electrode used [31].Lower sexual dysfunction rates after PAE is an important finding as these complications significantly impact patients' QOL and well-being.As mentioned, both TURP and OSP involve prostatic tissue resection, resulting in more immediate symptom improvements compared to PAE.Accordingly, the included studies reflect an overall higher surgical reintervention rate in PAE groups compared to TURP.This outcome was reported by 3 of 6 studies comparing PAE with TURP [19,20,24].The literature reports that approximately 20-36% of PAE patients experience clinical failure, commonly requiring subsequent intervention to promote symptom improvements [32,33].Rates of clinical failure can vary depending on the study population and inclusion criteria; however, factors with strong predictive power for PAE success or failure still remain unclear and require further study [34].Additionally, differences in PAE techniques such as embolic particle sizes may lead to differences in success rates between studies.Embolic particle sizes ranged from 250-500 microns in the included studies.A meta-analysis examining the relationship between embolic particle size and PAE outcome determined that smaller embolic particles were associated with a more notable reduction in IPSS at 12-months [35].However, it should be noted that the optimal particle size has yet to be determined and study protocols and outcomes for PAE remain quite varied.
Furthermore, reintervention and failure rates can be influenced by several factors.In our study, Abt et al. 2021 [19], observed that 25% of their cases underwent unilateral embolization, although no direct cause of failure was reported.In Carnevale's study, 13.3% of patients in the oPAE group had unilateral embolization, attributed to severe atherosclerosis or occlusion of the IVA on one side [20].According to Costa and colleagues [33], one crucial factor for procedural failure is the presence of non-target embolization, which can significantly impact the efficacy of the procedure.More specifically, the complexity of prostatic arterial anatomy and the occurrence of collateral formation can challenge the success of PAE and potentially lead to the need for reintervention [36].Technical aspects also play a pivotal role in PAE success.Gao et al., reported clinical failure rates of 9.4% for PAE patients, with a technical failure rate of 5.3%, suggesting higher failure rates may be linked to varying levels of expertise among urologists and interventional radiologists [21].Bilhim et al. highlighted the importance of procedural accuracy in PAE.The study indicates that precise catheterization and embolization of both prostatic arteries are crucial for reducing reintervention rates.Incomplete or inaccurate embolization can result in persistent symptoms, leading to the need for further treatment [37].
There is some concern about the potential longterm consequences of radiation exposure from PAE [38].As reflected in the included studies, PAE involves a longer procedure time than TURP and OSP, with a mean radiation exposure time of approximately 20-58 min [39].While PAE has been proven to be an effective treatment for LUTS associated with BPH, this procedure's reliance on ionizing radiation presents a risk that has not been studied extensively yet [40].However, the longer procedure time for PAE ranging from 84-144.8 min compared to 59-83.5 min for TURP in the present included studies has been found to be more favourable in reducing the risk of blood loss and other serious complications reported when directly resecting and ablating prostatic tissue [41].
Most of the included studies did not present longterm comparative data, except for two studies by Abt et al. [19] and Gao et al. [21] which evaluated PAE and TURP at 24 months.Future RCTs are needed to establish the comparative long-term effects and benefits of these procedures.However, according to a longer-term study by Pisco et al. which evaluated PAE outcomes up to 6.5 years, the clinical success rate has been reported to be about 76% for PAE [42].Furthermore, a study by Carnevale et al. reported a 23% symptom recurrence at 72 months for PAE patients [43].Abt et al. demonstrated that the reduction of PV was less pronounced after PAE than TURP after 24-month follow up [19].
The present work differs from previous published systematic reviews published with respect to treatment modalities, methodology, inclusion criteria, outcomes, and demographics.We have reported the most recent evidence published on the efficacy of PAE compared with surgical and minimally invasive options for BPH.We reported clinical outcomes which used validated tools (IIEF questionnaire and IPSS-QoL scale), contributing to the reliability and objectivity of these results.
The reported studies indicate that PAE might improve BPH symptoms and urodynamic measures; however, the long-term comparative effectiveness of these procedures is not clearly established.PAE stands as an effective minimally invasive procedure for males with moderate to severe BPH who might not be suitable candidates for surgery for reasons such as advanced age or comorbidities.Future long-term studies are needed to provide more evidence regarding the effectiveness and safety of PAE compared with other treatments for BPH.

Limitations
Some of the studies did not report all of the outcomes included in this review which limits the comparison of the evidence.In addition, some studies did not report 95% CIs, so values were estimated using WebPlotDigitizer [44] and standard deviations were imputed for studies that did not report variance using a conservative formula (correlation coefficient of 1).Risk of bias was a concern for most of the included studies.Some of the RCTs were underpowered and included smaller sample sizes; did not clearly define methods for randomization; and confounding factors were not always accounted for.Study populations and designs differed, limiting the ability to effectively compare the studies.Further, most of the included studies lacked long-term follow-up aside from two studies by Abt et al. [19] and Gao et al. [21] and so the evidence regarding the prospective symptom improvement in the PAE group is uncertain.
Lastly, the heterogeneity noted in our meta-analysis, as evidenced by high I 2 values for certain outcomes, points to the diversity in the included studies' designs, patient demographics, and intervention methods.To manage this, we utilized random-effects models, which account for variance among studies, thus providing a refined estimation of the effects that respects the heterogeneity of the data.A methodological strength of our analysis is the exclusive pooling studies from the same design measuring outcomes at the same time point.Non-randomized studies were addressed descriptively, due to the presence of only one study which precluded pooling.Should more non-randomized studies have been available, they would have been aggregated together.This careful selection enhances the robustness of our findings, although the heterogeneity observed reminds us to consider these results within the appropriate clinical contexts.

Conclusion
This systematic review includes the available comparative evidence on the use of PAE for BPH.Only RCTs and observational studies comparing PAE with TURP or OSP were included.The collected data shows that PAE might improve symptomatic BPH-LUTS; reduce adverse events and major complications; and provide an alternative option for males with BPH who cannot undergo surgery or have failed medical therapy.Whether PAE is more effective than TURP and OSP remains uncertain, thus ongoing, longer-term studies will provide valuable evidence of the effectiveness and safety of PAE compared with other BPH treatment options.

Table 1 (
continued) Data for procedure time reported as mean (standard deviation) or mean ± standard deviation unless otherwise specified Abbreviations: RCT randomized controlled trial, SD standard deviation, TURP transurethral resection of the prostate, BPH benign prostatic hyperplasia, OSP open simple prostatectomy, PAE prostatic artery embolization, MRI magnetic resonance imaging, PV prostate volume, GFR glomerular filtration rate, IPSS International Prostate Symptom Score, LUTS lower urinary tract symptoms, PErFecTED proximal embolization first then embolize distal method of prostatic artery embolization, M-TURP monopolar transurethral resection of the prostate, B-TURP bipolar transurethral resection of the prostate, PVA polyvinyl alcohol Qmax peak urinary flow rate, QOL quality of life, NR not reported a Data reported as median (range)

Table 7
Post-void residual volume (PVR) for prostatic artery embolization (PAE) vs. open simple prostatectomy (OSP) Abbreviations: CI confidence interval, NA not applicable, NR not reported

Table 9
Adverse events for prostatic artery embolization (PAE) vs transurethral resection of the prostate (TURP) classified by Clavien-Dindo Grade Abbreviations: NR not reported, PErFecTED Proximal embolization first then embolize distal method of PAE, M-TURP monopolar transurethral resection of the prostate, B-TURP bipolar transurethral resection of the prostateAdverse Event

Table 10
Adverse events of studies comparing prostatic artery embolization (PAE) with open simple prostatectomy (OSP)

Table 11
Embolization particle size, prostate volumes (PV) and radiation dose Data are mean (standard deviation) unless otherwise indicated Abbreviations: TAUS transabdominal ultrasound, TRUS transrectal ultrasound, MRI Magnetic Resonance Image, NR not reported oPAE, original PAE, PErFecTED Proximal Embolization First Then Embolize Distal, SD Standard Deviation a Data for Ray et al. 2018 displayed as median (interquartile range)